A major mechanism of lipid deposition in the blood vessel is believed that monocytes and macrophages infiltrate into the injured vascular endothelial cells, and thereby these cells incorporate oxygenated low density lipoproteins (LDL) in excess and turn into the so-called foam cells that have accumulated droplets of cholesterol esters (Ross R., Nature 362: 801, 1993). It is thought that foam cells, together with T cells and vascular smooth muscle cells, form fatty streaks, and the interaction between the cells facilitates pathological processes, generating vascular lesions such as arteriosclerosis including atherosclerosis.
In many epidemiological studies in recent years, hyperlipemia has been defined as a risk factor of arteriosclerosis, and in fact various drugs that regulate blood levels of lipids such as cholesterol and triglyceride have been reported. For example, drugs such as Plavastatin that suppress cholesterol biosynthesis by inhibiting 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) have been widely used. These drugs can indeed lower lipid levels in the blood during the administration period, but various problems have been pointed out: once the administration is suspended the level returns to the level before administration; the effect is not adequate in patients with severe high-cholesterolemia; or improvement in blood lipid levels does not always lead to life lengthening.
These drugs are also known to be associated with side effects such as myopathy and abnormal hepatic function, and are likely to inhibit the biosynthesis of physiological components such as ubiquinone and dolichol, raising a possibility to elicit an adverse effect. Other therapeutic agents of hyperlipemia include drugs that influence lipoprotein metabolism in the blood vessel such as Clofibrate, drugs that suppress the absorption of cholesterol from the intestinal tract such as Nicomol and Colestyramine, and the like. None of them, however, are satisfactory in terms of efficacy and side effects, and thus there is a need for the development of further excellent drugs in terms of efficacy and safety.
On the other hand, chymase is a serine protease that is widely distributed in the tissue such as the skin, the heart, vascular walls, intestinal tracts, etc. as a granular component in mast cell (Mast Cell Proteases in Immunology and Biology; Caughey, G. H., Ed; Marcel Dekker, Inc.: New York, 1995). Chymase is known to participate in a synthetic process independent of angiotensin converting enzyme in the conversion of angiotensin I to angiotensin II.
It is also reported that in the aorta of atherosclerosis or arterial aneurysm a chymase-dependent angiotensin II (AngII) forming activity was observed to be significantly higher than in the aorta without atherosclerosis or arterial aneurysm (M. Ihara, et al., Hypertension 32: 514-20, 1998) and that the expression of chymase mRNA is increased in the aorta of monkeys that were fed a high-cholesterol diet for 6 months (S. Takai, et al., FEBS Lett. 412: 86-90, 1997).
It has also been indicated that LDL can be restrictively degradated by chymase, and that the modified LDL binds to mast cell granules (Mast Cell Proteases in Immunology and Biology; Caughey, G. H., Ed; Marcel Dekker, Inc.: New York, 1995). LDL-granule complex is likely to be easily incorporated into macrophages. These clinical findings and experimental results implicate the involvement of intravascular chymase in atheroma formation, but the nole of chymase in pathological and physiological states has not been elucidated and the study to clarify this point has just begun. In recent years, search for substances that inhibit chymase activity are underway in addition to the elucidation of physiological actions of chymase.
As chymase inhibitors, there have been reported: a low molecular weight chymase inhibitor described in a textbook (Protease Inhibitors; Barrett et al., Eds.: Elssevier Science B.V.: Amsterdam, 1996); reported as a peptidyl inhibitor, α-keto acid derivative (WO 93-25574, Proc. Natl. Acad. Sci. USA 92: 6738, 1995), α,α-difluoro-β-keto acid derivative (Japanese Unexamined Patent Publication (Kokai) No. 9-124691), a tripeptide inhibitor (WO 93-03625), and a phosphoric acid derivative (Oleksyszyn et al., Biochemistry 30: 485, 1991); as peptide-like inhibitors, a trifluoromethylketone derivative (WO 96-33974, Japanese unexamined Patent Publication (Kokai) No. 10-53579) and an acetamide derivative (Japanese Unexamined Patent Publication (Kokai) No. 10-7661, Japanese Unexamined Patent Publication (Kokai) No. 10-53579, Japanese Unexamined Patent Publication (Kokai) No. 11-246437, WO 99-41277, WO 98-18794, WO 96-39373); as non-peptidyl inhibitors, a triazine derivative (Japanese Unexamined Patent Publication (Kokai) No. 8-208654, Japanese Unexamined Patent Publication (Kokai) No. 10-245384), a phenolester derivative (Japanese Unexamined Patent Publication (Kokai) No. 10-87567), a cephem derivative (Japanese Unexamined Patent Publication (Kokai) No. 10-87493), an isoxazole derivative (Japanese Unexamined Patent Publication (Kokai) No. 11-1479), an imidazolidine derivative (WO 96-04248), a hydantoin derivative (Japanese Unexamined Patent Publication (Kokai) No. 9-31061), a quinazoline derivative (WO 97-11941), and the like. However, no drugs or therapeutic regimens have been established that employ the inhibition of chymase activity as a therapeutic strategy.